Tris-phenyl ethylene compounds



Patented Oct. 16, 1951 UNITED STATES PATENT *OFFICE "TR1S PI-IENYLETHYLEN-E' GOMPOUNDS Robert S. SheltonQMariemohtQ and; Marcus G. VanCampen, Jr Wyoming, Ohio, assignors to Cincinnati;

Oliib; a corporation of Delaware N Drawing.= Applicati onc0ctob'en 25,51947, Serial-No. 782,232-

rcrafms; "(01. fish ets)" The new eompouhdsare indicated for'the treatment of atrop-hic rhinitis"; amenorrhoea," atrcphic'" vulvovaginitis;inhibition of lactation; and inth'etreatment of the menopause:This"appli'cation is a" coi'i'tinuation-"ih part of our application Ser;No.384,58' i, filed- Marc-n21, "1941.

The new compounds include tris-p-hydroxyphenyl ethylene and certainderivatives thereof which may be represented by thestructural formula:

in which eaclrR is a radical selected from the group consisting ofhydroxy, alkoxy, acyl-oxy, and senz oyl-oxy at least one 'ofwhichishydroxyl; The alkoiry derivatives include those in which the alkylradicals pfthe ethergroupings are aliphatic residues of low nolecularweight.- The acyl-0xy derivatives are'thosein whichthe acylradicals areresidues of low molecular weight aliphatic acids. In th newcompoundsthefR- subs't'i'tuents' need not be the same, but? one or moremay be difierent sothat mixed compounds result; e. g. compoundscontaining one or more hydroxy groups with'theremainder ether orestergroups, or compound s containing one or more ether groups with theremainder ester groups. Those compounds in which'R representshydroxy' oralkoxy are particularly advantageous for therapeutic use although theesters have the advantage of prolonged activity as comparedto the othercompounds.

In general, these compounds arewell defined crystalline material's,quite soluble in'oil and practically insolubleinwat'er. "The compoundsin which R is'h'ydTOXy are Somme irfaqiiebil's al k841i.

I As pointed out above'the newcofiipouhdsa're highly activetherapeutically. They pbssess the advantage of an extremelysmall"thieshold es teiogenic' activity combined withdiiw toiricity.

The new compounds may bej repareddmm simplerstructures byvariousaddition and conde'n'sation reactions. For example, the tiiSf-D alkoxyderivatives are conveniently prepardity' the reaction of 4',4'-di'-a11oxybenzoph. non 1th an alkoxybenzyl magnesium halide aria-orig:

drated'to the ethylene compound; Also a'r'ifa'p propriatedesoxy-alkox'ybnzoin maybereaeteu' with a desired alkoxyphenylmagnesiumhalide,

, according-to the Grignard procedure, followed by deli dfatibi'idf'tl'ie resulting alcohol.

halide" u onwhe' hYZifOXy "d'e'riVatiVc.

F p=hydroxyphenyl ethylene may be produced f romzthe: tris-methoxycompound throughde-etherificationr byv means of strongalkalihydrol-ysisc Mixedcompoundsscontaining both hydroxy:*and ethergroupings. may be 1 produced in a step-wisei-reactionincluding theaddition, of: a lfi di-oxy. derivative of benzophenone andya- Grignand'reagentilprepared' fronrthez oxy derivative of an aralkyl\halidefollowedtby dehydration. of the =res'ulting a'lcoholto the ethylenecompound. The' OXY-SllbStitrlltfidag-IOUDS are selected with a view toselective-=c=leavage. to the I desired mixed hydroxy-ether derivatives.For. example; in the r presenoe of. methylmagnesium iodideain: ethersolution the aralkoxy groups are cleaved while the alkoxy roups remainuntouched. The ester derivatives "mayflo'e' -prepares by conventionalmethods, e. gi athesreaction eithezhydroxy compounds with controlledamounts of acid anhydrides "or acid chlorides. Thebenzoyhcoi'npcu'nus'are" fbrrnedby the reaction of the b enzoy-l The new compounds arep'urified'by 'conventional' extiaifl tibh,'distlllationandrecrystallization"methods;

Preparation of "exemplary individuals of the? newcompounds' will beillustrated in thefollo'w ing' examples, but the invention isnot'lirnited" thereto:

EX A MP LE' 1' lflii-bisi phZ/dTOl'Z/Ph'ftZ/ZZ -"(p-*anisyl) -ethylene43f dibenzyloiiybenzophenone" is prepared "by the'reaction' of 4,4dihydroiiybenzophenone and benzyl chloridei'n the presence ofpotassiuinihy= droxide. Itseparates from benzene i'ncolorl-ess plates,M'J'P; 184-185'C. 700"partsof a'n.0;36N

solutibn'of p meth'oxybenzylmagnesium chlbride' to 800 parts on a steambath. Chilling givesap A suspension of 97 parts of this ethanol in 525parts of 85% phosphoric acid is stirred for 4 hours on a steam bath.Dilution with an equal volume of water causes a gummy solid to separate.Recrystallization from acetone gives ap proximately 77 parts ofcolorless needles, 'M. P. 80-82" C.

To a suspension of 5 parts of the resulting ethylene in 160 parts ofether is added 15 parts of a 2.5 N solution of methylmagnesiumiodide.The ether is removed by distillation and the residue is heated for 5hours on the steam bath. The frothy solid is decomposed with excessdilute ammonium chloride solution before the organic material isextracted with ether. Phenolic material is extracted from the ether withdilute sodium hydroxide solution. The addition of excess carbon dioxide(Dry Ice) to the alkaline solution causes the solution to separate.Recrystallization from benzene gives colorless needles of1,1-bis-p-hydroxyphenyl-2-(p-anisyl) -ethylene, M. P. 184-185 C.

EXAMPLE 11 1,2 bis (p-hydrorypheneyl) -1- (p-anisyl) ethylene Thiscompound is prepared by the analogous reaction of 4 methoxy, lbenzyloxybenzophenone with benzyl chloride in the presence of potassiumhydroxide. The resulting ketone is reacted with an excess ofp-benzyloxybenzylmagnesium chloride solution to yieldl,2-bis(pbenzyloxyphenyl)-l-(p-anisyl) ethanol. This compound isdehydrated to the corresponding ethylene by stirring a suspension of itin 85% phosphoric acid at steam bath temperatures. The resulting1,2-bis(p-benzyloxyphenyl) -l-(panisyl)ethylene is treated by heatingwith an excess of methylmagnesium iodide solution at steam bathtemperatures to yield the final product.

EXAMPLE III 1,1,2-tris (p-acetomyphenyl) ethylene A solution of 24 partsof p-anisoyl anisole in 40 parts of hot benzene is poured with stirringinto 160 parts of cold absolute ether. To the resulting suspension offinely divided anisoyl anisole is added 22 parts of p-methoxy benzylmagnesium chloride in about 250 parts of ether. The latter reagent isadded with stirring over a period of about one hour, after which thereaction mixture is poured into 150 parts of water containing 37 partsof ammonium chloride and 5 parts of 28% aqueous ammonia. The upper etherlayer is separated and evaporated on the steam cone. The residue isrecrystallized from hot alcohol containing a little ammonia.Tris-p-methoxyphenyl ethanol is obtained in about 75-85% yield, M. P.130-13l C. The ethanol compound is placed in a Claisen flask with a fewcrystals of sulfamic acid or toluene sulfonic acid and slowly warmedunder a pressure of to 20 mm. until eifervescence ceases. The residualoil is then poured into 150 to 300 parts of ligroin and warmed until itdissolves. This solution is then treated with decolorizing carbon, andis allowed to stand for several days. Tris-p-methoxyphe'nyl ethyleneseparates in white clusters of needle-dike crystals, M. P. 100-101 C.The yield is about 85%.

A suspension of 34.? parts of tris(p-methoxyphenyl) ethylene and 100parts of potassiumhydroxide in 400 parts of ethanol is shaken in anautoclave at 200 C. for 24 hours. The mate- 4 rial is diluted with 1000parts of water before the ethanol is distilled off on a steam bath. Theresulting aqueous solution is chilled, acidified with concentratedhydrochloric acid and extracted with ether. The ether extract is washed,dried and concentrated on a steam bath. Esterification of the residualoil is accomplished by refluxing for 4 hours with a mixture of 98 partsof pyridine and 108 parts of acetic anhydride.

The reaction mixture is poured into 2000 parts of water and the oil isextracted with chloroform. The chloroform solution is washed with dilutesodium hydroxide and water, dried and concentrated on a steam bath.Recrystallization of the residue from a mixture of benzene and petroleumether gives 20 parts of 1,l,2-tris(pacetoxyphenyl) ethylene in the formof colorless needles, M. P. l35-l37 C.

EXANIPLE IV 1,1,2-tris (p-hydroxyphenyl) ethylene A suspension of 8.6parts of tris(p-acetoxyphenyl) ethylene in 200 parts of 10% potassiumhydroxide solution is refluxed for 5 hours. Acidification with aceticacid gives an oil which gradually solidifies. Recrystallization fromxylene gives about 4.3 parts of pale yellow needles, melting at 159 to191 C. when thoroughly dry.

EXAMPLE V 1,1 -di-p-anisyl-2- (p-hydroryphenyl) ethylenep-Benzyloxybenzyl alcohol is prepared by treating p-hydroxybenzylalcohol with benzyl chloride in the presence of potassium hydroxide. itseparates from ligroin in colorless plates, M. P. 87-88 C. A suspensionof 64 parts or p-oenzyloxybenzyl alcohol in 600 parts of ether issaturated With dry hydrogen chloride at a temperature below 10 C. Thesolution is left for 12 hours at 50 C. before the solvent is evaporatedupon a steam bath. Recrystallization of the residue from ligroin gives63 parts of p-benzyloxyphenyl chloride as colorless plates, M. P. 76-78C.

- The Grignard reagent is prepared from 11.6 parts of p-benzyloxybenzylchloride and 7.2 parts of magnesium in 200 parts of ether and is addeddropwise, with stirring to a refluxing solution of 10.5 parts of4,4-dimethoxybenzophenone in parts of benzene for 2 hours and renuxed.The mixture is decomposed with excess ammoniurn chloride solution. Theorganic layer is separated, made alkaline with ammonia and concentratedto parts on a steam bath. Chilling gives approximately 11 parts ofcrystals of 1,1- di-p-anisy1-2-(p-benzyloxyphenyl) ethanol, M. P. -124C. After recrystallization from ethanol the material melted at 123 to125 C. The suspension of 9 parts of this ethanol in parts of 85%phosphoric acid is stirred for 4 hours on the steam bath. The suspensionis diluted with water and filtered. Recrystallization of the solid fromethanol gives 7.8 parts of colorless needles, M. P. 139-141" C. Asolution of 6 parts of the resulting1,1-di-p-anisyl-2-(p-benzyloxyphenyl) ethylene and 30 parts ofconcentrated hydrochloric acid in 200 parts of glacial acetic acid isheated'on a steam bath for 2 hours. The solvents are removed bydistillation under reduced presfurther purification crystalline1,1-di-(p-anisyl) 2 (p-hydroxyphenyl) ethylene results.

5 v 6 We claim: 5. 1,1-di-p-lower alkoxyphenyl 2 nydroxy- 1. Compoundsof the formula: phenyl ethylene.

6. 1,1 bis-p-hydroxyphenyl-Z-p-anisyl-ethyl- C=CHOR 5 7.1,1-bis-p-anisy1- 2 p-hydroxyphenyl ethyl- O ROBERT S. SHELTON. in whicheach R is a radical selected from the MARCUS VAN CAMPEN' groupconsisting of hydroxy, lower alkoxy, low- I er aliphatic carboxy, andbenzoyl-oxy, with the m REFERENCES CITED proviso that at least one of thradi al R, i The following references are of record in the hydroxyl.file of this patent:

g- -pygroxfyptllilenyl ethylene. f th UNITED sTATEs PATENTS ompoun s o ec ass consis ng o e mono lower alkyl and the di lower alkyl ethers of 15Number Name Date 2,301,260 Davies et a1. Nov. 10, 1942ms'p'hydmxyphenylethylene- 2346 049 Rohrmann Apr 4 1944 4.1,1-bis-p-hydroxypheny1-2-p-1ower alkoxypheny1 ethy1ene 2,430,891Shelton et a1 Nov. 18, 1947 Patent No. 2,571,954

6 sa me may conform to th gned and sealed this 29 Certificate ofCorrection for 2-hydroxyread 2-p-hydrowy-;

abent should be read e record of th day of as corrected above, the casein the Patent Oflice.

January, A. D. 1952.

1. COMPOUNDS OF THE FORMULA: